Transient Receptor Potential (TRP) ion channels or receptors constitute a superfamily of cation channels that consists of 28 members with a wide range of physiological functions. TRP receptors have been classified into seven subfamilies viz., TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin) and TRPN(NOMPC) families.
TRPA1, also known as ANKTM1, is a large transmembrane protein of 1119 amino acids in human with six predicted membrane-spanning domains and a single pore loop characteristic of all other TRP receptor proteins. TRPA1 possesses a long N-terminal region with up to 18 predicted ankyrin repeats. TRPA1 is believed to be most closely related to TRPV3, and is more closely related to TRPV1 and TRPV2 than to TRPV5 and TRPV6.
It is believed TRPA1 is expressed in nociceptive neurons, which sense the peripheral damage and transmit pain signals and on C fibers in the bronchopulmonary region. TRPA1 is membrane bound, and most likely acts as a heterodimeric voltage gated channel. TRPA1 plays a variety of pathophysiological roles as a sensor of irritating chemicals and cold, and is a participant in both airway inflammation and airway hyper-responsiveness.
The TRPA1 receptor activation in the airways by noxious stimuli, including cold temperatures (generally, less than about 17° C.), pungent natural compounds (e.g., mustard, cinnamon and garlic), tobacco smoke, tear gas and environmental irritants, is supposed to be one of the mechanisms for neurogenic inflammation in the airways. Neurogenic inflammation is an important component of chronic airway diseases like chronic obstructive pulmonary disease (“COPD”) and asthma.
Activation of TRPA1 receptor by its agonists is reported to cause pain, neuropeptide release, and neurogenic inflammation and airway sensory responses. Signaling events downstream of TRPA1 activation include intracellular Ca+2 modulation, release of inflammatory cytokines and neuropeptide release, in general plasma extravasation, bronchoconstriction, and respiratory depression during respiratory disease condition in particular. TRPA1 antagonists would abrogate the TRPA1 receptor mediated downstream signaling events. TRPA1 receptor blockade is perceived as a novel strategy for therapeutic intervention of pain and respiratory disorders.
Respiratory disorders related to airway inflammation include a number of severe lung diseases including asthma and COPD. The airways of asthmatic patients are infiltrated by inflammatory leukocytes, of which the eosinophil is believed to be the most prominent component. Inflammatory sensitization of airway neurons is believed to increase nasal sensitivity, heighten the sense of irritation, and promote fluid secretion, airway narrowing, and bronchoconstriction.
Oxidative stress is a hallmark of most acute and chronic inflammatory airway conditions, including viral infections, asthma, rhinitis, and COPD. TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma as well as COPD. Endogenous TRPA1 agonists, including reactive oxygen species (ROS) and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma. During inflammation, ROS are generated by infiltrating macrophages and neutrophils.
PCT Application Publication Nos. WO 2004/055054, WO 2005/089206, WO 2007/073505, WO 2008/0949099, WO 2009/089082, WO 2009/002933, WO 2009/158719, WO 2010/109334, WO 2009/144548, WO 2010/004390, WO 2010/109287, WO 2010/109329, WO 2010/109328, WO 2010/125469 and WO 2011/114184 describe various transient receptor potential (“TRP”) receptor modulators.